Journal
NEUROBIOLOGY OF DISEASE
Volume 127, Issue -, Pages 492-501Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2019.04.004
Keywords
Genetic variance; Dementia; Lewy bodies; Genetic correlation
Categories
Funding
- Alzheimer's Society
- Lewy Body Society
- National Institutes of Neurological Disease and Stroke
- Neuroscience Research Australia
- University of New South Wales - South West Dementia Brain Bank
- BRACE (Bristol Research into Alzheimer's and Care of the Elderly)
- Brains for Dementia Research
- Medical Research Council [MR/N026004/1]
- Medical Research Council (MRC)
- Brains for Dementia Research (BDR) (Alzheimer Society)
- Autistica UK
- NIHR Oxford Biomedical Research Centre - Wellcome Trust
- Canadian Consortium on Neurodegeneration in Aging
- CERCA Programme/Generalitat de Catalunya
- ARUK
- Big Lottery Fund
- Taub Institute
- Panasci Fund
- Parkinson's Disease Foundation
- NIH [AG05131]
- Michael J. Fox Foundation for Parkinson's Research, NINDS R01 [NS078086]
- Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS) [NS072187]
- Little Family Foundation
- Mangurian Foundation Program for Lewy Body Dementia
- Alzheimer's disease Research Center [P50 AG016547]
- Mayo Clinic Rochester
- National Institute on Aging [P50 AG016574, U01 AG006786]
- Queen Square Brain Bank at the UCL Institute of Neurology - ARUK senior fellowship
- MRC London Neurodegenerative Diseases Brain Bank
- Brains for Dementia Research project - Alzheimer's Society
- (ARUK)
- NIHR UCLH Biomedical Research Centre
- Queen Square Dementia Biomedical Research Unit
- Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [AG000951-12]
- Penn Alzheimer's Disease Core Center [AG10124]
- Penn Morris K. Udall Parkinson's Disease Research Center [NS053488]
- French program Investissements d'avenir [ANR-10-IAIHU-06]
- Helsinki University Central Hospital
- Folkhalsan Research Foundation
- Finnish Academy
- National Institutes of Health [R01NS037167, R01CA141668, P50NS071674]
- University of Wisconsin Transdisciplinary Tobacco Use Research Center [P50 DA019706, P50 CA084724]
- Intramural Research Program of the National Institutes of Health (National Institute of Neurological Disorders and Stroke) [ZIA NS003154]
- Johns Hopkins Morris K. Udall Center of Excellence for Parkinson's Disease Research [NIH P50 NS38377]
- Johns Hopkins Alzheimer's disease Research Center [NIH P50 AG05146]
- Canadian Institute for Health Research
- Krembil Foundation
- Babcock Memorial Trust
- Ann Arbor Veterans Affairs Hospital
- International Genomics of Alzheimer's Project (IGAP) - French National Foundation on Alzheimer's disease and related disorders
- LABEX (laboratory of excellence program investment for the future) DISTALZ grant
- Inserm
- Institut Pasteur de Lille, Universite de Lille 2
- Lille University Hospital
- Alzheimer's Research UK [503176]
- Wellcome Trust [076113, 085475, 090355]
- German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) [01GI0102, 01GI0711, 01GI0420]
- NIH/NIA [U01 AG032984, U24 AG021886, U01 AG016976]
- AGES [N01-AG-12100]
- NHLBI [R01 HL105756]
- Icelandic Heart Association
- Erasmus Medical Center and Erasmus University
- Alzheimer's Association [ADGC-10-196728]
- Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS)
- National Institute on Aging (NIA)
- National Institute of Environmental Health Sciences
- National Institutes of Health, Department of Health and Human Services [1ZIA-NS003154, Z01-AG000949-02, Z01-ES101986]
- Department of Defense [W81XWH-09-2-0128]
- Michael J Fox Foundation for Parkinson's Research
- American Parkinson's disease Association (APDA)
- Barnes Jewish Hospital Foundation
- Greater St Louis Chapter of the APDA
- Hersenstichting Nederland
- Prinses Beatrix Fonds
- KORA (Cooperative Research in the Region of Augsburg)
- Forschungszentrum fur Umwelt and Gesundheit - German Federal Ministry of Education, Science, Research
- State of Bavaria - National Genome Research Network (NGFNplus) [01GS08134]
- (German Federal Ministry for Education and Research)
- German Federal Ministry of Education and Research [NGFN 01GR0468]
- (PopGen) [01EW0908]
- EU Joint Programme Neurodegenerative Diseases Research (JPND) project under the aegis of JPND
- BMBF [01ED1406]
- iMed - the Helmholtz Initiative on Personalized Medicine
- French National Agency of Research [ANR-08-MNP-012]
- France-Parkinson Association
- Assistance Publique-Hopitaux de Paris (PHRC) [AOR-08010]
- Landspitali University Hospital Research Fund
- Icelandic Research Council
- European Community Framework Programme 7, People Programme
- IAPP on novel genetic and phenotypic markers of Parkinson's disease and Essential Tremor (MarkMD) [PIAP-GA-2008-230596]
- Michael J. Fox Foundation
- (Biomedicum, University of Helsinki)
- UK replication cases on ImmunoChip
- WTCCC2 project - Wellcome Trust [083948/Z/07/Z, WTCCC1]
- Wellcome Trust disease centre [WT089698/Z/09/Z]
- Parkinson's UK [8047, J-0804]
- Michael J Fox Foundation
- Department of Health's National Institute for Health Research Biomedical Research Centres
- Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award [WT089698]
- Medical Research Council Protein Phosphorylation Unit at the University of Dundee
- National Institute on Aging, NIH, Bethesda, MD, USA
- University of California Healthcare
- MRC [UKDRI-1009, G0701075, MR/L016397/1, G1001799, MR/N026004/1, MR/L023784/2, G0901254, G1001253, MR/L022656/1, MR/J004758/1, G1100540, MR/K01417X/1, UKDRI-3003, G0400074, G0502157, G0900652] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PhD2014-16, ART-PPG2009A-1, ART-PG2010-1, ART-PPG2011A-14] Funding Source: researchfish
- Medical Research Council [UKDRI-1009, G1001253, MR/L501542/1, G0901254, G0701075, MR/N026004/1, MR/K01417X/1, MR/J004758/1] Funding Source: researchfish
- Parkinson's UK [J-0804, G-1307] Funding Source: researchfish
- Rosetrees Trust [M733] Funding Source: researchfish
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [ZIANS003154] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [ZIAAG000936] Funding Source: NIH RePORTER
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Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.
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